IL-10 suppresses CD2-mediated T cell activation via SHP-1.
Interleukin (IL)-10 is an essential suppressive cytokine and plays a key role in peripheral T cell tolerance to allergens, autoantigens, transplantation antigens and tumor antigens. However, the molecular mechanisms of direct T cell suppression by IL-10 are not fully understood. Here, we demonstrate that IL-10 directly inhibits CD2 signaling in T cells. T cell stimulation via CD2 alone induces activation and proliferation, when endogenous IL-10 sources are eliminated from cultures. IL-10 utilizes the src-homology-2 domain containing tyrosine phosphatase (SHP-1) to directly suppress T cell activation. The role of SHP-1 in IL-10-mediated suppression of CD2 co-stimulation on T cells is demonstrated by using dominant-negative SHP-1 over-expressing T cells and silencing endogenous SHP-1 by small inhibitory RNA. Findings are confirmed using both SHP-1-deficient mice and IL-10-deficient mice. CD2-induced proliferation is suppressed by exogenous IL-10 in IL-10-deficient, but not SHP-1-deficient murine T cells. In conclusion, SHP-1-mediated inhibition of CD2 signaling represents a novel mechanism for direct T cell suppression by IL-10.
Taylor
Alison
A
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland. at504@cam.ac.uk
Verhagen
Johan
J
Akkoç
Tunç
T
Wenig
Renate
R
Flory
Egbert
E
Blaser
Kurt
K
Akdis
Mübeccel
M
Akdis
Cezmi A
CA
D000818:Animals; D018801:CD2 Antigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D018801:CD2 Antigens; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6